Flexible Bone Composite

ABSTRACT

The present invention relates in general to implantable flexible bone composites, and method for preparing the same. The flexible bone composite includes at least one polymeric layer and at least one calcium-containing layer. The polymeric layer can be a polymeric layer including a synthetic polymer. The calcium-containing layer can include a calcium compound such as β-Ca 3 (PO 4 ) 2 . The flexible bone composites of the invention are useful as bone void fillers and have improved handling characteristics.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of prior provisional applicationSer. No. 60/578,610 filed on Jun. 10, 2004, which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present invention includes flexible bone composites including atleast one polymeric layer and at least one calcium-containing layer, andmethods for making the same. The composites of the invention haveimproved handling characteristics.

BACKGROUND OF THE INVENTION

An area of interest with regard to bone cements or calcium phosphatecompositions focuses on reinforcing bone cements with various materials.Often ceramic bone cements, though strong, are brittle and notsufficiently resistant to catastrophic failure (e.g., through cracking)to function as a matrix material. Polymers can be used to reinforceceramic bone components. For example, implantable composite materialscontaining a strong and resilient matrix impregnated with reinforcingfiller particles, whiskers, or meshes are known. Resorbable implantmaterials, such as polylactides and polyglycolides, compared totraditional, non-resorbable metal or composite materials, for example,have the advantage of being biocompatible, of being biodegradable aftera period of time, and of not requiring removal, e.g., in bone fixationor repair applications. These qualities can be useful for implantmatrices that are designed to be temporary place fillers (and in somecases, stabilizing components) for healing and/or regrowth, e.g., ofbone voids or defects.

SUMMARY OF THE INVENTION

The present invention includes flexible bone composites including atleast one polymeric layer and at least one calcium-containing layer.

In one embodiment, the flexible bone composite includes: (a) a polymericlayer having a first side and a second side; and (b) a firstcalcium-containing layer affixed or physically and/or chemicallyattached to the first side of the polymeric layer.

In another embodiment, the flexible bone composite includes: (a) aperforated polymeric layer having a first side and a second side; and(b) a calcium-containing layer affixed or physically and/or chemicallyattached to the first side of the polymeric layer.

The invention also includes methods for making a flexible bone compositeincluding at least one polymeric layer and at least onecalcium-containing layer.

In one embodiment, the invention includes a method for making a flexiblebone composite including a polymeric layer having a first side and asecond side, including: disposing a calcium compound onto the first sideof the polymeric layer to form a first calcium-containing layer.

In another embodiment, the invention includes a method for making aflexible bone composite including a polymeric layer having a first sideand a second side, including: contacting a first calcium compound withthe first side of the polymeric layer to form a first intermediatecomposite; and heating the first intermediate composite at a temperaturesufficient to affix or to physically and/or chemically attach the firstcalcium compound to the first side of the polymeric layer and provide afirst calcium-containing layer.

In another embodiment, the invention includes a method for making aflexible bone composite including a polymeric layer having a first sideand a second side, including: casting a solution including the polymerand a solvent onto a release surface; allowing the solution to gel;contacting a calcium compound with a first side of the gel; and allowingthe solvent to evaporate from the gel to form a flexible bone compositehaving a first calcium-containing layer affixed or physically and/orchemically attached to the first side of the polymeric layer.

In another embodiment, the invention includes a method for making aflexible bone composite including a perforated polymeric layer having afirst side and a second side, including: perforating a polymeric layerto form a perforated polymeric layer; heating the perforated polymericlayer; contacting a first calcium compound with the first side of theperforated polymeric film to form a first intermediate composite; andallowing the first intermediate composite to cool to a temperaturesufficient to affix or to physically and/or chemically attach the firstcalcium compound to the first side of the perforated polymeric layer andprovide a calcium-containing layer.

In another embodiment, the invention includes methods for treating ahard tissue defect in a patient in need thereof.

In another embodiment, the invention includes a method for treating abone defect in a patient in need thereof, including: implanting atherapeutically effective amount of a flexible bone composite includingat least one polymeric layer and at least one calcium-containing layerinto the defect.

In another embodiment, the present invention includes a flexible bonecement composition that can be molded to fill voids such as, e.g., bonevoids, and a method for making such composition. In another embodiment,the invention includes a flexible calcium-containing composite materialfor implantation that exhibits improvements in key mechanical propertiesas a result of a specific combination of properties of the ingredients.

In another embodiment, the present invention also includes kitsincluding a container which contains a flexible bone composite includingat least one polymeric layer and at least one calcium-containing layer.

The details of the invention are set forth in the accompanyingdescription and examples below. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, illustrative methods andmaterials are now described. Other features, objects, and advantages ofthe invention will be apparent from the description and from the claims.In the specification and the appended claims, the singular forms alsoinclude the plural unless the context clearly dictates otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a cross-sectional view of an embodiment of the flexiblebone composite of the invention having a polymeric layer and acalcium-containing layer.

FIG. 2 depicts a cross-sectional view of an embodiment of a flexiblebone composite of the invention having a first calcium containing layer,a polymeric layer, and second calcium-containing layer.

FIG. 3 depicts a cross-sectional view of an embodiment of a flexiblebone composite of the invention having a first polymeric layer, acalcium-containing layer, and a second polymeric layer.

FIG. 4 a depicts a perspective view of an embodiment of a polymericlayer of the invention, where the layer is perforated with holes.

FIG. 4 b depicts a perspective view of an embodiment of a polymericlayer of the invention, where the layer is perforated with slits.

FIG. 5 depicts a cross-sectional view of a multilayer flexible bonecomposite of the invention having a first flexible bone composite and asecond flexible bone composite.

FIG. 6 depicts a cross-sectional view of an exemplary flexible bonecomposite of the invention having a polymeric layer and acalcium-containing layer, where the composite is rolled up.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As noted above, the present invention includes a flexible bone compositeincluding at least one polymeric layer and at least onecalcium-containing layer. Generally, the at least one polymeric layerhas a first side and a second side and the at least onecalcium-containing layer is disposed at least on the first side of theat least one polymeric layer.

The polymeric layer includes a polymer. The polymer can be a resorbablepolymer, a non-resorbable polymer, or a combination thereof. In oneembodiment, the polymeric layer contains less than about 10% by weightof non-resorbable polymer, preferably less than about 5% by weight ofnon-resorbable polymer, more preferably less than about 1% by weight ofnon-resorbable polymer, based on the total weight of the polymericlayer.

In a preferred embodiment, the polymeric layer includes a resorbablepolymer, and the polymeric layer is substantially free of anon-resorbable polymer. Preferably, the resorbable polymeric layer isresorbable in vivo and includes a resorbable polymer.

The polymer in the polymeric layer can include a synthetic polymer, anon-synthetic polymer (i.e., a polymer obtained from a plant or animal),or a combination thereof. In one embodiment, the polymeric layerincludes a synthetic polymer, and the polymeric layer is substantiallyfree of non-synthetic polymer. For example, the polymeric layer maycontain less than about 10% by weight of non-synthetic polymer,preferably less than about 5% by weight of non-synthetic polymer, morepreferably less than about 1% by weight of non-synthetic polymer, basedon the total weight of the polymeric layer.

In one embodiment, the flexible bone composite includes a polymericlayer including a synthetic polymer and a calcium-containing layer.

In another embodiment, the flexible bone composite includes: (a) apolymeric layer including a synthetic polymer, wherein the polymericlayer is substantially free of non-synthetic polymer; and (b) acalcium-containing layer. As used herein, the phrase “substantiallyfree” should be understood to mean that less than about 0.5% by weightof the substantially free component is present, preferably less thanabout 0.2% by weight, more preferably less than about 0.1% by weight,and often none.

In another embodiment, the flexible bone composite includes: (a) apolymeric layer including a synthetic polymer, wherein the polymericlayer is substantially free of non-synthetic polymer and substantiallyfree of non-resorbable polymer; and (b) a calcium-containing layer.

In one embodiment, the flexible bone composite includes: (a) a polymericlayer including a synthetic resorbable polymer and having a first sideand a second side; and (b) a first calcium-containing layer affixed orchemically and/or physically attached to the first side of the polymericlayer.

In another embodiment, the flexible bone composite includes: (a) morethan one polymeric layer, at least a first polymeric layer, preferablyan exterior layer, including a synthetic non-resorbable polymer andhaving a first side and a second side, wherein the first polymeric layeris substantially free of resorbable polymer, and at least a secondpolymeric layer, preferably an interior layer, including a resorbablepolymer and having a first side and a second side; and (b) a firstcalcium-containing layer affixed or chemically and/or physicallyattached at least to the first side of the first polymeric layer and atleast to the first side of the second polymeric layer.

As used herein, the term “polymer” includes homopolymers and copolymers(i.e., polymers including two or more different monomeric units). Asused herein, the generic term “copolymer” includes, but is not limitedto, alternating copolymers, random copolymers, block copolymers, or anycombination thereof.

In one embodiment, the polymeric layer contains less than about 25% byweight of calcium-containing compound based on the total weight of thepolymeric layer. In another embodiment, the polymeric layer containsless than about 10% by weight of calcium-containing compound based onthe total weight of the polymeric layer. In another embodiment, thepolymeric layer contains less than about 1% by weight ofcalcium-containing compound based on the total weight of the polymericlayer. Preferably, the polymeric layer is substantially free of calciumcompounds.

Examples of polymers useful for preparing the polymeric layer include,but are not limited to, homopolymers or copolymers of monomers selectedfrom L-lactide; L-lactic acid; D-lactide; D-lactic acid; glycolide;α-hydroxybutyric acid; α-hydroxyvaleric acid; α-hydroxyacetic acid;α-hydroxycaproic acid; α-hydroxyheptanoic acid; α-hydroxydecanoic acid;α-hydroxymyristic acid; α-hydroxyoctanoic acid; α-hydroxystearic acid;hydroxybutyrate; hydroxyvalerate; β-propiolactide; β-propiolactic acid;γ-caprolactone; β-caprolactone; ε-caprolactone; γ-butyrolactone;pivalolactone; tetramethylglycolide; tetramethylglycolic acid;dimethylglycolic acid; trimethylene carbonate; dioxanone; those monomersthat form liquid crystal polymers; those monomers that form cellulose;those monomers that form cellulose acetate; those monomers that formcarboxymethylcellulose; those monomers that formhydroxypropylmethyl-cellulose; polyurethane precursors includingmacrodiols selected from polycaprolactone, poly(ethylene oxide),poly(ethylene glycol), poly(ethylene adipate), poly(butylene oxide), anda mixture thereof, isocyanate-functional compounds selected fromhexamethylene diisocyanate, isophorone diisocyanate, cyclohexanediisocyanate, hydrogenated methylene diphenylene diisocyanate, and amixture thereof, and chain extenders selected from ethylenediamine,1,4-butanediol, 1,2-butanediol, 2-amino-1-butanol, thiodiethylene diol,2-mercaptoethyl ether, 3-hexyne-2,5-diol, citric acid, and a mixturethereof, and any combination of two or more of the foregoing.

In one embodiment, the polymeric layer includes resorbable polymers.Non-limiting examples of resorbable polymers include, e.g., polymersderived from monomers selected from L-lactic acid, D-lactic acid,L-lactide, D-lactide, D,L-lactide, glycolide, a lactone, a lactam,ε-caprolactone, trimethylene carbonate, a cyclic carbonate, a cyclicether, para-dioxanone, beta-hydroxybutyric acid, beta-hydroxypropionicacid, beta-hydroxyvaleric acid, saccharides, collagen, fibrin, albumin;and any combination of two or more of the foregoing.

In another embodiment, the polymeric layer includes a resorbablesynthetic polymer. Non-limiting examples of resorbable syntheticpolymers include, e.g., a poly(L-lactide) (co)polymer, apoly(D,L-lactide) (co)polymer, a polyglycolide (co)polymer, apolycaprolactone (co)polymer, a poly(tetramethylglycolic acid)(co)polymer, a polydioxanone (co) polymer, a polyhydroxybutyrate(co)polymer, a polyhydroxyvalerate (co)polymer, apoly(L-lactide-co-glycolide) copolymer, a poly(glycolide-co-trimethylenecarbonate) copolymer, a poly(glycolide-co-caprolactone) copolymer, apoly(glycolide-co-dioxanone-co-trimethylene carbonate) copolymer, apoly(tetramethylglycolic acid-co-dioxanone-co-trimethylene carbonate)copolymer, a poly(glycolide-co-caprolactone-co-L-lactide-co-trimethylenecarbonate) copolymer, a poly(lactide-co-caprolactone) copolymer, apoly(hydroxybutyrate-co-hydroxyvalerate) copolymer, a liquid crystal(co)polymer, a combination thereof, or a copolymer thereof.

In one embodiment, the polymeric layer includes apoly(L-lactide-co-glycolide) copolymer.

In another embodiment, the polymeric layer includes monomers selectedfrom L-lactide; D-lactide, D,L-lactide, ε-caprolactone, trimethylenecarbonate; para-dioxanone, and any combination of two or more of theforegoing.

In another embodiment, the polymeric layer includes a copolymer ofL-lactide and ε-caprolactone.

In another embodiment, the polymeric layer includes a copolymer of 70%L-lactide and 30% ε-caprolactone (e.g., 70:30poly(L-lactide-co-ε-caprolactone)).

In one embodiment, the poly(L-lactide-co-glycolide) copolymer includesat least about 15% of glycolide repeat units and at least about 15% ofL-lactic acid repeat units. In another embodiment, thepoly(L-lactide-co-glycolide) copolymer includes about 82% of glycoliderepeat units and about 18% of L-lactic acid repeat units. In anotherembodiment, the poly(L-lactide-co-glycolide) copolymer includes about18% of glycolide repeat units and about 82% of L-lactic acid repeatunits.

In another embodiment, the polymeric layer includes a non-resorbablepolymer. Non-limiting examples of non-resorbable polymers include, e.g.,polyethylene, polypropylene, and polyurethanes.

The polymeric layers are commercially available or can be made bypolymerizing the various types of monomers (e.g., L-lactide, glycolide)using any suitable method such as those described below. When thepolymeric layers includes two or more different monomers, i.e., acopolymer, any method capable of forming the copolymer such that thebiodegradation or resorbability and the mechanical properties (e.g.,before and during implantation) are sufficient for the requirements ofthe application for which the copolymer is to be used. For example, onesuch polymerization method can be found in U.S. Pat. No. 6,096,855, theentire disclosure of which is incorporated herein by reference hereto.Other examples of copolymerization methods for producingpoly(D,L-lactide-co-glycolide) and other random copolymers are disclosedin U.S. Pat. No. 4,157,437 and International Publication No. WO97/36553, the entire disclosures of which are also incorporated hereinby reference hereto.

Advantageously, in one embodiment, the polymers from which the polymericlayer is formed must have a sufficient molecular weight to be able toperform (e.g., mechanically) in the desired application. Generally, asufficiently high molecular weight can be obtained by polymerizingsubstantially all (i.e., preferably at least about 98 mol %, morepreferably at least about 99 mol %, most preferably at least about 99.5mol %) of the monomeric and/or dimeric copolymer substituents. As usedherein, the term “molecular weight” should be understood to mean extentof polymerization, or number or weight average of monomeric or dimericunits in the copolymer chains. Molecular weight, as used herein, can beapproximated by a number of known methods, e.g., such as by gelpermeation or size exclusion chromatography (GPC or SEC), by inherent orintrinsic viscosity analysis (I.V.), or by an equivalent scientifictechnique through which a correlation can be made to estimate copolymermolecular weight.

When measured by GPC or SEC against polystyrene standards, the polymersaccording to the invention (before being processed or fabricated intofilms) can, in one embodiment, exhibit a number average molecular weightof at least about 75,000 grams/mole, for example from about 150,000grams/mole to about 1,000,000 grams/mole or from about 250,000grams/mole to about 900,000 grams/mole. Such measurements can, inanother embodiment, also yield a weight average molecular weight of atleast about 125,000 grams/mole, for example at least about 250,000grams/mole or from about 400,000 grams/mole to about 2,500,000grams/mole. Alternately, in some embodiments, the number averagemolecular weight can be between about 16,000 grams/mole and about 75,000grams/mole or between about 18,000 grams/mole and about 50,000grams/mole, and the number average molecular weight can be between about50,000 grams/mole and about 150,000 grams/mole or between about 60,000grams/mole and about 120,000 grams/mole.

In another embodiment, such measurements can also show a polydispersity(i.e., a ratio of weight average molecular weight to number averagemolecular weight) from about 1.3 to about 3.5, for example from about1.6 to about 2.8 or from about 1.85 to about 2.5. The desiredapplication for which the polymeric layers will be used should generallydetermine the acceptable range of molecular weight values, e.g., acopolymer used for drug delivery, maxillofacial implant, or otherapplication in which enhanced biodegradation or resorbability isparamount, may be preferred to exhibit number average and/or weightaverage molecular weights in a lower region of, or even below, theranges listed above, whereas a copolymer used in a pin, rod, anchor,staple, or other mechanically-intensive and/or load-bearing applicationmay be preferred to exhibit number average and/or weight averagemolecular weights in an intermediate or upper region of, or even above,the ranges listed above.

When measured for I.V. at a concentration of about 0.1% w/v inchloroform, the polymers according to the invention (before beingprocessed or fabricated into layers) can, in one embodiment, exhibit aninherent viscosity of at least about 1.0 dl/g, for example from about2.5 dug to about 8 dl/g, from about 3 dl/g to about 7 dl/g or from about4 dl/g to about 6.5 dl/g. In another embodiment, the inherent viscosityof the poly(L-lactide-co-glycolide) copolymer of the invention can begreater than about 4.5 dl/g. The desired application for which thepolymers will be used should generally determine the acceptable range ofinherent viscosity values, e.g., a copolymer used for drug delivery,maxillofacial implant, or other application in which enhancedbiodegradation or resorbability is paramount, may be preferred toexhibit lower inherent or intrinsic viscosities than those listed above,whereas films used in a composite for a pin, rod, anchor, staple, orother mechanically-intensive and/or load-bearing application may bepreferred to exhibit inherent or intrinsic viscosities within, or evenabove, those listed above.

The polymers can have a low moisture (or water) content (i.e., beforebeing combined with the calcium compound-containing component), forexample, not more than about 1.5% by weight or not more than about 1% byweight. In one embodiment, the moisture or water content can be not morethan about 500 ppm, for example not more than about 250 ppm or not morethan about 150 ppm. In other embodiments, the moisture or water contentof polymers according to the invention can be not more than about 200ppm or not more than about 100 ppm.

In some embodiments, the polymers can be subject to a drying and/orvolatile organic compound (VOC) removal step, in order to remove water,organic solvent(s), unreacted monomer/dimer, or other low molecularweight and/or volatile impurities or compounds that can be present inthe polymers. This drying/removal step can include, but is not limitedto, introduction of a relatively-dry, inert gas (e.g., such as drynitrogen, argon, or the like, or a mixture containing such a gas),application of a vacuum (e.g., such that the pressure is not more thanabout 10 Torr, for example more than about 5 Ton or not more than about1 Ton:), application of an increased temperature (e.g., of at leastabout 50° C., for example at least about 65° C. such as from about 70°C. to about 120° C., and also preferably, provided that the copolymer isat least partially crystalline, that the increased temperature is notgreater than about 5° C. below its melting temperature, for example notgreater than about 10° C. below its melting temperature), or anycombination thereof. This drying/removal step is generally undertakenfor a period of time sufficient to render the moisture content withinacceptable or preferred limits. When performed, the step canadvantageously include a combination of application of increasedtemperature and application of a vacuum and occurs for at least about 4hours, for example for at least about 12 hours, or alternately for notmore than about 24 hours or from about 16 hours to about 20 hours.

The polymers can exhibit a wide range of degrees of crystallinity, withpreferable values depending upon the desired application for which theyare to be used. In one embodiment, the polymeric layers aresemicrystalline and can exhibit a degree of crystallinity from about 15%to about 30%, for example from about 20% to about 30%, or for examplefrom about 20% to about 26%. In another embodiment, the layers of theinvention can exhibit a degree of crystallinity of less than about 15%.In an alternate embodiment, the layers of the invention can exhibit adegree of crystallinity from about 15% to about 50%. In other alternateembodiments, the layers of the invention can exhibit a degree ofcrystallinity of less than about 10%, less than about 5%, less thanabout 1%, or can exhibit substantially no crystallinity (i.e., less thanabout 0.5%, preferably less than about 0.1%, or at any rate notquantitatively detectable by one or more experimental methods). The“degree of crystallinity” can be measured by a number of well-knownexperimental techniques and, when the term is used herein, reflects therelative proportion, by volume, cross-sectional area, or linear paththrough a sample, of crystalline regions in comparison tonon-crystalline or amorphous regions of the films. Suitable experimentaltechniques to measure degree of crystallinity include, but are notlimited to, differential scanning calorimetry (DSC), x-ray scattering ordiffraction methods (e.g., XRD, WARD, WARS, etc.), or the like.

The polymers may also exhibit a wide range of degrees of crystallineperfection (or crystalline imperfection), again with preferable valuesdepending upon the desired application for which they are to be used.The degree of crystalline perfection or imperfection can be measured,for example, by DSC or another well-known experimental technique and canbe referred to herein in terms of a heat of fusion (ΔH_(f)), whichrepresents the relative perfection or imperfection of the crystals ofthe copolymer in terms of the amount of energy per unit of material(e.g., in Joules per gram, J/g, or milliJoules per milligram, mJ/mg)required to melt, or de-crystallize, the crystals of the copolymer. Inone embodiment, the films of the invention are semicrystalline and canexhibit a heat of fusion of less than about 50 J/g, for example lessthan about 30 J/g or less than about 25 J/g. In another embodiment, thefilms of the invention can exhibit a heat of fusion from about 50 J/g toabout 70 J/g. In alternate embodiments, the films of the invention canexhibit a heat of fusion of from about 0.5 J/g to about 15 J/g, fromabout 0.1 J/g to about 10 J/g, from about 15 J/g to about 25 J/g, or canexhibit substantially no heat of fusion (i.e., less than about 0.1 J/g,or at any rate not quantitatively detectable by one or more experimentalmethods).

Melting temperatures and glass transition temperatures for the polymerscan also vary, with preferable values depending upon the desiredapplication for which they are to be used. Melting and glass transitiontemperatures can be measured, for example, by DSC or another well-knownexperimental technique, and are generally dependent upon the rate atwhich temperature is increased or decreased. Standard DSC tests areperformed with temperature changing at a rate of about 5° C./min toabout 20° C./min, particularly at about 10° C./min. The meltingtemperature of the polymeric layers of the present invention, asmeasured by standard DSC tests, can, in one embodiment, be between about90° C. and about 225° C., for example from about 110° C. to about 165°C. or from about 130° C. to about 150° C. The glass transitiontemperatures of the polymers, as measured by standard DSC tests, can, inanother embodiment, be between about 30° C. and about 100° C., forexample between about 40° C. and about 60° C.

Values for various mechanical properties of the polymers can varywidely, depending inter alia upon the desired application for which theyare to be used and the process by which they are formed into articles ordevices for said applications. For example, in one embodiment, thetensile strength of the polymers can range from about 10 to about 100MPa. In another embodiment, the elastic modulus of the polymers canrange from about 0.1 to about 6 GPa.

As the polymers and/or compositions have utility in implantations and invivo applications, it may be desirable to sterilize such polymers and/orcomposites to minimize in vivo response, e.g., from infection, foreignbody rejection, or the like. Because the resorbable polymers of theinvention are resorbable or degradable in the presence of water,sterilization methods other than autoclaving are particularlyappropriate. Such sterilization processes can include, but are notlimited to, exposure to ethylene oxide, exposure to γ-radiation,exposure to an electron beam source, exposure to a cold (or at leastlow-temperature) plasma source, or a combination thereof. Thesterilization process, depending upon the exposure dose and duration, isone possible way to introduce branching, grafting, or crosslinking tothe polymers.

In one embodiment, single or multiple doses to these means ofsterilization can be performed on the polymers, articles, or devicesaccording to the invention in an amount, or in amounts, sufficient toprevent, inhibit, or curtail in vivo response. In one preferredembodiment, the sterilization includes a single dose exposure toradiation or ethylene oxide. In another preferred embodiment, thesterilization includes a single dose exposure of thepoly(L-lactide-co-ε-caprolactone) copolymers or composites according tothe invention to γ-radiation of about 25 kGy.

When the resorbable polymeric layer includes resorbable polymers, theflexible bone composites containing them tend to exhibit complete invivo or in vitro resorption from about 1 month to about 2.5 years, forexample from about 2 months to about 2 years. As used herein, “completeresorption” refers to the situation where, upon visual inspection, thereis either no evidence of polymeric material at the site of implantation,or where, upon analysis of a sample of the implantation site of thedegraded polymer, there is an absence of oligomeric material resultantfrom degradation of the polymer that has a number average molecularweight of more than about 1,000 grams/mole or not more than about 500grams/mole. In another embodiment, the polymers and/or compositionsaccording to the invention should typically retain at least a portion oftheir mechanical properties after implantation in vivo or after exposureto a phosphate buffered saline (PBS) solution having a pH of about 7.4(±0.2) at a temperature of about 37° C. (±1° C.).

The polymeric layer can be prepared by methods known in the art. Forexample, in one embodiment, the polymeric layer can prepared usingconventional viscoelastic-liquid forming or liquid-setting meansincluding, but not limited to, extrusion, compression molding, injectionmolding, thermoforming, blow molding, rotational molding, calendaringand casting (see, e.g., Joel R. Fried, Polymer Science and Technology,pages 373-384 (1995), and K. J. Mackenzie, “Film and Sheeting Materials”in 10 Kirk Othmer: Encyclopedia of Chemical Technology 775-787 (1993),the entire contents of each of the foregoing references beingincorporated herein by reference).

For example, in another embodiment, the polymeric layer can be preparedby compression molding or calendaring.

In one embodiment, the polymeric layer is in the form of a film.

The amount and thickness of the polymeric layer can vary. In general,the polymeric layer is present in an amount sufficient to provide aflexible platform for the calcium-containing layer(s). In oneembodiment, the polymeric layer is present in an amount ranging fromabout 1% by weight to about 99% by weight based on the total amount ofthe flexible bone composite. In another embodiment, the polymeric layeris present in an amount ranging from about 10% by weight to about 75% byweight based on the total amount of the flexible bone composite. Inanother embodiment, the polymeric layer is present in an amount rangingfrom about 25% by weight to about 30% by weight based on the totalamount of the flexible bone composite.

The polymeric layer(s) may be of any suitable thickness(es). Forexample, the polymeric layer can have a thickness ranging from about0.01 mm to about 1.0 mm. In one embodiment, the polymeric layer has athickness ranging from about 0.05 mm to about 0.5 mm. In anotherembodiment, the polymeric layer has a thickness ranging from about 0.05mm to about 0.25 mm. In a preferred embodiment, the polymeric layer hasa thickness ranging from about 0.05 mm to about 0.15 mm.

In one embodiment, the polymeric layer may be perforated with one ormore perforations. Such perforations may provide pathways for liquids topenetrate the polymeric layer. The perforations may be of any size andshape and distributed in any pattern. For example, in some embodiments,the perforations can be distributed homogeneously over the polymericlayer. When the polymeric layer is perforated, in one embodiment, theextent of perforation can range from about 1% to about 90% by area basedon the total surface area of the first or second side of the polymericlayer; in another embodiment, the extent of perforation can range fromabout 5% to about 75% by area based on the total surface area of thefirst or second side of the polymeric layer; and in another embodiment,the extent of perforation can range from about 15% to about 50% by areabased on the total surface area of the first or second layer of thepolymeric layer. In a preferred embodiment, the extent of perforation isabout 22% by area based on the total surface area of the first or secondlayer of the polymeric layer.

Methods for perforating the polymeric layer include, but are not limitedto, punching holes through the polymeric layer using a punch, a die, acalendering roller, or slitting the polymeric layer with a knife orscalpel.

The diameter of the holes in the perforated layer can vary or can bewithin a predetermined tolerance. In one embodiment, the diameter of theholes ranges from about 0.4 mm to about 6.5 mm; in another embodiment,the diameter of the holes ranges from about 0.8 mm to about 3.5 mm; andin another embodiment, the diameter of the holes ranges from about 1.0mm to about 2 mm. In a preferred embodiment, the diameter of the holesis about 1.5 mm.

In certain embodiments, where the polymeric layer is perforated byslicing the film with a knife or scalpel, the length of the cuts orslits can vary. In one embodiment, the length of the cut ranges fromabout 0.5 to about 10 mm; in another embodiment, the length of the cutranges from about 1 to about 5 mm; and in another embodiment, the lengthof the cut ranges from about 2 to about 3 mm.

In one embodiment, the invention includes a flexible bone compositeincluding: (a) a perforated polymeric layer having a first side and asecond side; and (b) a first calcium-containing layer affixed orphysically and/or chemically attached to the first side of the polymericlayer. In another embodiment, the invention includes a flexible bonecomposite including: (a) a perforated resorbable polymeric layer havinga first side and a second side; and (b) a first calcium-containing layeraffixed or physically and/or chemically attached to the first side ofthe resorbable polymeric layer.

In another embodiment, the flexible bone composite includes a secondresorbable polymeric layer. In another embodiment, the second polymericlayer can be affixed or physically and/or chemically attached to thesecond side of the polymeric layer or the first calcium-containinglayer. Non-limiting examples of polymeric layers useful for making thesecond polymeric layer include homopolymers or copolymers discussedabove for the polymeric layer.

In one embodiment, the second polymeric layer is resorbable and includesa synthetic polymer.

In another embodiment, the second polymeric layer is perforated, asdescribed above for the polymeric layer.

In yet another embodiment, the second resorbable polymeric layer is notperforated.

The thickness of the second polymeric layer can be any suitablethickness, as described above for the polymeric layer. In oneembodiment, the polymeric layer and the second polymeric layer have thesame thickness. In another embodiment, the thickness of the polymericlayer and the second polymeric are different.

As noted above, the flexible bone composite includes a firstcalcium-containing layer including a calcium compound. Thecalcium-containing layer can be affixed or physically and/or chemicallyattached to at least one side, such as the first side, of the polymericlayer. Methods of affixing or physically and/or chemically attaching thecalcium-containing layer on the polymeric layer are described below.

The calcium compounds can be porous or non-porous. The term “porous”includes, but is not limited to, macroporosity (mean pore diametergreater than or equal to 100 microns), mesoporosity (mean pore diameterless than 100 microns but greater than or equal to 10 microns) andmicroporosity (mean pore diameter less than 10 microns).

The pores may be of any size, shape or distribution, or within apredetermined tolerance. In addition, the pores can be interconnectingor non-interconnecting. In one embodiment, the diameter of the pores canrange in size up to about 750 microns. In another embodiment, thecalcium compound is porous with pore sizes ranging up to about 500microns, with approximately 75% of the pores being at least 100 micronsin size and the remaining 25% of the pores being no more than 10 micronsin size.

In cases where the calcium compound is affixed or physically and/orchemically attached to the polymeric layer, a majority of the externalsurface of the calcium compound is not covered with polymer. The limitedexternal coverage of the calcium compounds may provide for enhancedresorption.

In one embodiment, the calcium-containing layer contains less than about25% by weight of polymer based on the total weight of thecalcium-containing layer. In another embodiment, the calcium-containinglayer contains less than about 10% by weight of polymer based on thetotal weight of the calcium-containing layer. In another embodiment, thecalcium-containing layer contains less than about 1% by weight ofpolymer based on the total weight of the calcium-containing layer.Preferably, the calcium-containing layer is substantially free ofpolymer.

In one embodiment, the calcium compounds have less than about 5% byweight, preferably less than 1% by weight, more preferably less than0.5% by weight, of hydroxyapatite based on the total weight of thecalcium compound. In another embodiment, the calcium compound issubstantially free of hydroxyapatite.

In another embodiment, the calcium-containing layer can include anycalcium bone cement. Non-limiting examples of useful calcium compoundsinclude calcium phosphates, calcium sulfates, calcium carbonates, or anycombination thereof. Preferably, the calcium compound is a calcium salt.

In one embodiment, the first calcium-containing layer includes a calciumphosphate. Non-limiting examples of calcium phosphates includesamorphous calcium phosphate, crystalline calcium phosphate, or anycombination thereof.

In another embodiment, the first calcium-containing layer includescalcium phosphate,

wherein the calcium phosphate is CaHPO₄.nH₂O, α-Ca₃(PO₄)₂,α-bar-Ca₃(PO₄)₂, β-Ca₃(PO₄)₂, Ca₅(PO₄)₃OH, Ca₁₀(PO₄)₆(OH)₂, Ca₄O(PO₄)₂,CaP₄O₁₁, Ca₂P₂O₇, Ca(H₂PO₄)₂.nH₂O, Ca₈H₂(PO₄)₆.nH₂O, or any combinationthereof, where n is a number ranging from 0 to 5.

In another embodiment, the first calcium-containing layer includesβ-Ca₃(PO₄)₂.

In another embodiment, the first calcium-containing layer includesβ-Ca₃(PO₄)₂, wherein the β-Ca₃(PO₄)₂ is substantially free ofhydroxyapatite.

In another embodiment, the first calcium-containing layer includes acalcium sulfate. The calcium sulfate can be amorphous or crystalline.Non-limiting examples of useful calcium sulfates include Ca(SO₄),α-Ca(SO₄).½H₂O, β-Ca(SO₄).½H₂O, or any combination thereof.

The calcium compounds used in the present invention can be of any shapeincluding, for example, spherical, cubic, wedge-shaped, oblong,cylindrical, or combinations thereof. In one embodiment, the calciumcompounds are spherical. In another embodiment, the calcium compoundsare cubic.

The calcium compounds may be particles or granules of any size or shape.The granules are available commercially or can be obtained by grindingor milling a calcium compound to a desired particle size or particlediameter. The granules can be classified by, for example, sieving, toobtain the desired range of particle diameters (see Perry's ChemicalEngineering Handbook, chapter 21, pages 13-19 (Don. W. Green ed. 1984)).

In one embodiment, the mean diameter of the granules range in size fromabout 0.05 mm to about 10 mm. In another embodiment, the mean diameterof the granules range in size from about 0.075 mm to about 5 mm. Inanother embodiment, the mean diameter of the granules range in size fromabout 0.075 mm to about 1 mm. In another embodiment, the mean diameterof the granules range in size from about 1.4 mm to about 2.8 mm. Inanother embodiment, the mean diameter of the granules range in size fromabout 2.8 mm to about 5.6 mm. In another embodiment, the mean diameterof the granules range in size from about 0.1 mm to about 0.750 mm

The specific surface area of the calcium compounds can vary. Forexample, when the calcium compound is a granule, the specific surfacearea can range from about 0.1 m²/g to about 100 m²/g.

The amount and the thickness of the first calcium-containing layer canvary. In general, the amount of first calcium compound affixed orphysically and/or chemically attached to the first side of the polymericlayer is an amount sufficient to provide the desired therapeutic effectwhile still maintaining the desirable properties of the composition,e.g., flexibility and resistance to delamination.

In one embodiment, an amount of the calcium compound ranges from about1% to about 99% by weight based on the total weight of the flexible bonecomposite (i.e., the polymeric layer and the first calcium-containinglayer); in another embodiment, an amount of the calcium compound rangesfrom about 5% to about 95% by weight based on the total weight of theflexible bone composite; and in another embodiment, the amount of thecalcium compound ranges from about 70% to about 85% by weight based onthe total weight of the flexible bone composite.

In one embodiment, the first calcium-containing layer has a thicknessranging from about 0.05 mm to about 10 mm. In another embodiment, firstcalcium-containing layer has a thickness ranging from about 0.075 mm toabout 7.5 mm. In another embodiment, the first calcium-containing layerhas a thickness ranging from about 2.8 mm to about 5.6 mm. In anotherembodiment, the first calcium-containing layer has a thickness rangingfrom about 1.4 mm to about 2.8 mm. In another embodiment, the firstcalcium-containing layer has a thickness ranging from about 0.1 mm toabout 0.750 mm.

The density of calcium compound particles or granules disposed on orphysically and/or chemically attached to the first side of the polymericlayer can vary. That is, the spacing between the calcium compoundparticles, may vary. For example, in one embodiment, a majority of theparticles are within about 0.75 mm of at least one other calciumcompound particle. In another embodiment, a majority of the particlesare within about 0.25 mm of at least one other calcium compoundparticle. In another embodiment, a majority of the particles are withinabout 0.1 mm of at least one other calcium compound particle. In anotherembodiment, a majority of the particles are in contact with at least oneother calcium compound particle.

Any suitable thickness of the first calcium-containing layer can beused. For example, a first calcium compound granule having diameterapproximately equal to the desired thickness of the firstcalcium-containing layer is affixed or physically and/or chemicallyattached to a side of the polymeric layer as described below.

In addition, more than one calcium-containing layer may be used to formthe flexible bone composite. For example, the flexible bone compositemay include a second calcium-containing layer affixed or physicallyand/or chemically attached to the second side of the polymeric layer.

The second calcium-containing layer includes a second calcium compound.Non-limiting examples of useful second calcium compounds include thosedescribed above for the first calcium compounds. The second calciumcompound can be the same as, or different than, the first calciumcompound.

In one embodiment, the second calcium compound is substantially free ofhydroxyapatite. In one embodiment, the second calcium compound is acalcium salt.

In another embodiment, the second calcium compound is calcium phosphate.In another embodiment, second calcium compound is β-Ca₃(PO₄)₂. Inanother embodiment, the second calcium compound is β-Ca₃(PO₄)₂, wherethe β-Ca₃(PO₄)₂ is substantially free of hydroxyapatite.

The thickness of the second calcium layer can be the same as, ordifferent from, that of the first calcium-containing layer. In general,the thickness of the second calcium layer ranges from about 0.05 mm toabout 10 mm.

The flexible composite can be formed into any thickness or shape beforeor after implantation.

In some embodiments, moreover, two or more flexible composites can belayered upon each other to provide a thicker composite with multiplepolymeric layers and calcium-containing layers. For example, in oneembodiment, the multi-layer flexible bone composite can include: (a) afirst composite including: a first polymeric layer having a first sideand a second side; and a first calcium-containing layer affixed orphysically and/or chemically attached to the first side of the polymericlayer; and (b) a second composite including: a polymeric layer having afirst side and a second side; and a second calcium-containing layeraffixed or physically and/or chemically attached to the first side ofthe polymeric layer; wherein the first composite is affixed orphysically and/or chemically attached to the second composite to formthe multi-layer flexible bone composite that has alternating polymericlayers and calcium-containing layers. Additional composites may also beadded to form the multilayer flexible bone composite. The compositesused to make the multilayer flexible bone composite may be the same ordifferent. In some multilayer embodiments, it may be advantageous forone or more of the exterior layers to contain non-resorbable polymersand for the one or more interior layers to contain predominantlyresorbable polymers.

The multi-layer flexible bone composite can includes a porouscalcium-containing component, a nonporous calcium-containing component,or a combination thereof. In one embodiment, the multi-layer flexiblebone includes a porous calcium-containing component and a nonporouscalcium-containing component. In another embodiment, the multi-layerflexible bone includes a porous calcium-containing component.

The multi-layer flexible bone composite can includes a resorbablepolymeric layer, a non-resorbable polymeric layer, or a combinationthereof. Preferably, the multi-layer flexible bone composite includes atleast one resorbable polymeric layer including a synthetic polymer.

The plurality of composites may be affixed or chemically and/orphysically attached to each other using any suitable methods. Forexample, in one embodiment, when two or more flexible composites arelayered upon each, the resultant composite can optionally be heated. Forinstance, in some embodiments, the layered composites can be heated in aconvection oven for a time and a temperature sufficient to make thepolymeric layers tacky followed by cooling. In another embodiment,pressure is applied to the heated multi-layer composite.

In another embodiment, a flexible synthetic composite can be rolled up,e.g., like a jelly roll, to provide a thicker composite. In certainembodiments, it may be desirable for the portion of the rolled upcomposite that is on the exterior of the roll (e.g., on the outercircumference of the device shown in FIG. 6) to contain predominantlynon-resorbable polymer and for the portion of the rolled up compositethat is on the interior of the roll to contain predominantly resorbablepolymer.

In some embodiments, the flexible composites are malleable and moldable,and can be formed or cut into the desired shape before and/or duringimplantation. For example, in one embodiment, the flexible composite canbe cut into the desired size and/or shape using, e.g., a knife, shears,guillotine, or stamping with a die.

In one embodiment, the flexible composite is cut to the desired shapebefore implantation. In another embodiment, the flexible composite ismolded into the desired shape during implantation. In anotherembodiment, the flexible composite is cut to a shape beforeimplantation, and further molded during implantation.

Optionally, after fabrication, one or more surfaces of the flexible bonecomposites according to the invention may be treated to alter one ormore chemical and/or physical properties of the one or more surfaces,e.g., to increase the surface hydrophilicity or to decrease the watercontact angle. In one embodiment, the treatment can include exposure toan energy source capable of causing the one or more surfaces to becomereactive, e.g., radiation such as gamma rays, plasma (using, e.g., gasessuch as oxygen, carbon dioxide, argon, ammonia, nitrogen, or the like,or a combination thereof), or the like, or combinations thereof, eitherby themselves or in combination with exposure to another reactiveenvironment (e.g., presence of air, oxygen, ozone, or the like, exposureto chemically-reactive functional groups, or the like, or combinationsthereof).

In one embodiment, one or more surfaces of the flexible bone compositesaccording to the invention is treated with an oxygen plasma. In anotherembodiment, one or more surfaces of the flexible bone compositesaccording to the invention is treated with a carbon dioxide plasma.

In another embodiment, one or more surfaces of the flexible bonecomposites according to the invention is treated to form graftedsurface(s) according to the HYDROLAST™ process, commercially availablefrom AST Industries, Inc., of Billerica, Mass., in which the one or moresurfaces is exposed to a gas plasma such as oxygen, followed by reactionwith a polymeric/oligomeric compound, e.g., a poly(alkyleneoxide)/poly(alkylene glycol) such as PEO/PEG or a poly(alkylene imine)such as PEI.

Alternately or additionally, but also optionally, after fabrication, theflexible bone composites according to the invention may be aged, e.g.,through prolonged exposure to degradatory means such as heat. In oneembodiment, such optional processes can be performed, e.g., to alter thein vivo or in vitro degradation kinetics of the flexible bone compositesaccording to the invention, or to attain a desired set of chemicaland/or physical properties.

FIGS. 1 to 6 show examples of embodiments of the flexible bone compositeof the present invention where the calcium compound is in the form ofgranules. FIG. 1 depicts an exemplary flexible bone composite 10 of theinvention having a polymeric layer 30 and a calcium-containing layer 20including a calcium compound in the form of granules 22. The polymericlayer 30 has a first side 32 and a second side 34 and the granules 22are affixed or physically and/or chemically attached to the first side32 of the polymeric layer 30.

FIG. 2 depicts an embodiment of a flexible bone composite 10 having afirst calcium-containing layer 20 including granules 22, a polymericlayer 30, and a second calcium-containing layer 25 including granules22. As depicted in FIG. 2, the first calcium-containing layer 20 andsecond calcium-containing layer 25 are affixed or physically and/orchemically attached to the first side 32 and second side 34,respectively, of the polymeric layer 30.

FIG. 3 depicts an embodiment of a flexible bone composite 10 of theinvention having a first polymeric layer 30, a calcium-containing layer20 including granules 22, and a second polymeric layer 35. As depictedin FIG. 3, the calcium-containing layer 20 is disposed between the firstpolymeric layer 30 and the second polymeric layer 35.

FIGS. 4 a and 4 b depict embodiments of a polymeric layer 30 used in theflexible composite of the invention, wherein the polymeric layer 30 isperforated. In FIG. 4 a, the perforations 40 in the polymeric layer 30are substantially round. In FIG. 4 b, the perforations 42 in thepolymeric layer 30 are in the form of slits.

FIG. 5 depicts a multilayer flexible bone composite 50 having a firstcomposite 10 and a second composite 15 layered upon the first flexiblebone composition 10. In FIG. 5, a multilayer flexible bone composite 50is shown. The first composite 10 has a first polymeric layer 30 and asecond calcium-containing layer 20 including granules 22 affixed orphysically and/or chemically attached to one side of the polymeric layer30; and a second composite 15 has a second polymeric layer 35 and asecond calcium-containing layer 25 including granules 22 affixed orphysically and/or chemically attached to one side of the polymeric layer35.

FIG. 6 depicts an exemplary flexible bone composite 10 of the inventionhaving a polymeric layer 30 and a calcium-containing layer 20 includinggranules 22 affixed or physically and/or chemically attached to one sideof the polymeric layer 30, wherein the composite 10 is rolled up.

Optionally, a therapeutic substance such as, but not limited to, achemical therapeutic substance and/or a biological therapeutic substancecan be included in or on the flexible bone composite according to theinvention. In one embodiment, these therapeutic substances can bepresent in or on the calcium-containing layer, the polymeric layer, orboth. In another embodiment, the therapeutic substances can be added tothe respective layers, can be impregnated within the layers, can beadhered to the surfaces of the layers, or can be included as acontrolled release formulation within one or more of the layers.Non-limiting examples of the therapeutic substances include, but are inno way limited to, antimicrobials, antibiotics, chemotherapy drugs,growth factors (particularly osteoinductive growth factors) such as bonemorphogenetic proteins, endothelial cell growth factors, insulin-likegrowth factors, or the like, or a combination thereof.

When the therapeutic substance is an antimicrobial agent, one, andusually no more than three, usually no more than two, antimicrobialagents may be present in the flexible bone composite. Non-limitingexamples of useful antimicrobial agents include: Antiamebics, e.g.Arsthinol, Bialamicol, Carbarsone, Cephaeline, Chlorbetamide,Chloroquine, Chlorphenoxamide, Chlortetracycline, Dehydroemetine,Dibromopropamidine, Diloxanide, Diphetarsone, Emetine, Fumagillin,Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo-5-quinoline-sulfonic Acid,Iodochlorhydroxyquin, Iodoquinol, Paromomycin, Phanquinone,Polybenzarsol, Propamidine, Quinfamide, Scenidazole, Sulfarside,Teclozan, Tetracycline, Thiocarbamizine, Thiocarbarsone, Tinidazole;Antibiotics, e.g. Aminoglycosides (such as Amikacin, Apramycin,Arbekacin, Bambermycins, Butirosin, Dibekacin, Dihydrostreptomycin,Fortimicin(s), Gentamicin, Isepamicin, Kaniamycin, Micronomicin,Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin, Ribostamycin,Sisomicin, Spectinomycin, Streptomycin, Tobramycin, Trospectomycin),Amphenicols (Azidamfenicol, Chloramphenicol, Florfenicol,Thiamphenicol), Ansamycins (Rifamide, Rifampin, Rifamycin, Rifapentine,Rifaximin), .beta.-Lactams (Carbacephems, Loracarbef, Carbapenems(Biapenern, Imipenem, Meropenem, Panipenem), Cephalosporins (Cefaclor,Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, CefcapenePovoxil, Cefclidin, Cefdinir, Cefditoren, Cefepime, Cefetamet, Cefixime,Cefinenoxine, Cefodizime, Cefonicid, Cefoperazone, Ceforanide,Cefotaxime, Cefotiam, Cefozopran, Cefpimizole, Cefpiramide, Cefpirome,Cefpodoxime Proxetil, Cefprozil, Cefroxadine, Cefsulodin, Ceftazidime,Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime,Cefuzonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin,Cephaloridine, Cephalosporin, Cephalothin, Cephapirin Sodium,Cephradine, Pivcefalexin), Cephamycins (Cefbuperazone, Cefinetazole,Cefminox, Cefotetan, Cefoxitin), Monobactams (Aztreonam, Carumonam,Tigemonam), Oxacephens (Flomoxef, Moxalactam), Penicillins(Amdinocillin, Amdinocillin Pivoxil, Amoxicillin, Ampicillin,Apalcillin, Aspoxicillin, Azidocillin, Azlocillin, Bacampicillin,Benzylpenicillic Acid, Benzylpenicillin Sodium, Carbenicillin,Carindacillin, Clometocillin, Cloxacillin, Cyclacillin, Dicloxacillin,Epicillin, Fenbenicillin, Floxacillin, Hetacillin, Lenampicillin,Metampicillin, Methicillin Sodium, Mezlocillin, Naacillin Sodium,Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin GBenethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine,Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium,Penicillin G Procaine, Penicillin N, Penicillin 0, Penicillin V,Penicllin V Benzathine, Penicillin V Hydrabamine, Penimepicycline,Phenethicillin Potassium, Piperacillin, Pivampicillin, Propicillin,Quinacillin, Sulbenicillin, Sultamicillin, Talampicillin, Temocillin,Ticarcillin), Ritipenem), Lincosamides (Clindamycin, Lincomycin),Macrolides (Azithromycin, Capbomycin, Clarithromycin, Dirithromycin,Erythromycin, Erythromycin Acistrate, Erythromycin Estolate,Erythromycin Glucoheptonate, Erythromycin Lactobionate, ErythromycinPropionate, Erythromycin Stearate, Josamycin, Leucomycins, Midecamycins,Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin,Roxithromycin, Spiramycin, Troleandomycin), Polypeptides (Amphomycin,Bacitracin, Capreomycin, Colistin, Enduracidin, Enviomycin, Fusafungine,Gramicidin S, Gramicidin(s), Mikamycin, Polymyxin, Pristinamycin,Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine,Tyrothricin, Vancomycin, Viomycin, Virginiamycin, Zinc Bacitracin),Tetracyclines (Apicycline, Chlortetracycline, Clomocycline,Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline,Methacycline, Minocycline, Oxytetracycline, Penimepicycline,Pipacycline, Rolitetracycline, Sancycline, Tetracycline), Cycloserine,Mupirocin, Tuberin; synthetic antibacterial agents, e.g.2,4-Diaminopyrimidines (Brodimoprim, Textroxoprim, Trimethoprim),Nitrofurans (Furaltadone, Furazolium Chloride, Nifuradene, Nifuratel,Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol, Nitrofurantoin),Quinolones and Analogs (Cinoxacin, Ciprofloxacin, Clinafloxacin,Difloxacin, Enoxacin, Fleroxacin, Flumequine, Grepafloxacin,Lomefloxacin, Miloxacin, Nadifloxacin, Nadilixic Acid, Norflaxacin,Ofloxacin, Oxolinic Acid, Pazufloxacin, Pefloxacin, Pipemidic Acid,Piromidic Acid, Rosoxacin, Rufloxacin, Sparfloxacin, Temafloxacin,Tosufloxacin, Trovafloxacin), Sulfonamides (Acetyl Sulfamethoxpyrazine,Benzylsulfamide, Chloramine-B, Chloramine-T, Dichloramine T,N₂-Formylsulfisomidine, N₄—O-D-Glucosylsulfanilamide, Mafenide,4′-(Methylsulfamoyl)sulfanilanilide, Noprylsulfamide,Phthalylsulfacetamide, Phthalylsulfathiazole, Salazosulfadimidine,Succinylsulfathiazole, Sulfabenzamide, Sulfacetamide,Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine,Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole,Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic, Sulfamerazine,Sulfameter, Sulfamethazine, Sulfamethizole, Sulfamethomidine,Sulfamethoxazole, Sulfamethoxypyridazine, Sulfametrole,Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide,4-Sulfanilamidosalicylic Acid, N₄-Sulfanilylsulfanilamide,Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine,Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine,Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea,Sulfatolamide, Sulfisomidine, Sulfisoxazole), Sulfones (Acedapsone,Acediasulfone, Acetosulfone Sodium, Dapsone, Diathymosulfone,Glucosulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid,p-Sulfanilylbenzylamine, Sulfoxone Sodium, Thiazolsulfone), Clofoctol,Hexedine, Methenamine, Methenamine Anhydromethylenecitrate, MethenamineHippurate, Methenamine Mandelate, Methenamine Sulfosalicylate,Nitroxoline, Taurolidine, Xibomol; leprostatic antibacterial agents,such as Acedapsone, Acetosulfone Sodium, Clofazimine, Dapsone,Diathymosulfone, Glucosulfone Sodium, Hydnocarpic Acid, Solasulfone,Succisulfone, Sulfoxone Sodium, antifungal agents, such as AllylaminesButenafine, Naftifine, Terbinafine, Imidazoles (e.g., Bifonazole,Butoconazole, Cholordantoin, Chlormidazole, Cloconazole, Clotrimazole,Econazole, Enilconazole, Fenticonazole, Flutrimazole, Isoconazole,Ketoconazole, Lanoconazole, Miconazole, Omoconazole, OxiconazoleNitrate, Sertaconazole, Sulconazole, Tioconazole), Thiocarbamates(Tolcilate, Tolindate, Tolnaftate), Triazoles (Fluconazole,Itraconazole, Saperconazole, Terconazole), Acrisorcin, Amorolfine,Biphenamine, Bromosalicylchloranilide, Buclosamide, Calcium Propionate,Chlorphenesin, Ciclopirox, Cloxyquin, Coparaffinate, DiamthazoleDihydrochloride, Exalamide, Flucytosine, Halethazole, Hexetidine,Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione,Salicylanilide, Sodium Propionate, Sulbentine, Tenonitrozole, Triacetin,Ujothion, Undecylenic Acid, Zinc Propionate; and the like.

Other antimicrobial agents useful in the present invention includeQ-lactamase inhibitors (e.g. Clavulanic Acid, Sulbactam, Tazobactam);Chldramphenicols (e.g. Azidamphenicol, Chloramphenicol, Thiaphenicol);Fusidic Acid; synthetic agents such as Trimethoprim, optionally incombination with sulfonamides) and Nitroimidazoles (e.g., Metronidazole,Tinidazole, Nimorazole); Antimycobacterial agents (e.g. Capreomycin,Clofazimine, Dapsone, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin,Rifampicin, Streptomycin, Thioamides); Antiviral agents (e.g.Acryclovir, Amantadine, Azidothymidine, Ganciclovir, Idoxuridine,Tribavirin, Trifluridine, Vidarabine); Interferons (e.g. Interferon α,Interferon β); and antiseptic agents (e.g., Chlorhexidine, Gentianviolet, Octenidine, Povidone Iodine, Quaternary ammonium compounds,Silver sulfadiazine, Triclosan).

The therapeutic substance can further include a biological therapeuticsubstance, such as, e.g., a protein. In one embodiment, bone associatedproteins may be added to modify the physical properties of thecomposition, enhance resorption, angiogenesis, cell entry andproliferation, mineralization, bone formation, growth of osteoclastsand/or osteoblasts, or the like. Proteins of particular interest are thedifferent types of collagen, particularly Type 1. Other proteins includeosteonectin, bone sialoproteins (Bsp), alpha-2HS-glycoproteins, boneGla-protein (Bgp), matrix Gla-protein, bone phosphoglycoprotein, bonephosphoprotein, bone proteoglycan, protolipids, bone morphogenicproteins (e.g., BMP-1, -2A, -2B, -3, -3b, -4, -5, -6, -7, -8, -8b, -9,-10, -11, -12, -13, -14, -15), cartilage induction factor, plateletderived growth factor (PDGF-1, -2), endothelial cell growth factors(ECGF-1, -2a, -2b), skeletal growth factor (SKF═IGF-2), insulin-likegrowth factors (IGF-1, IGF-2), fibroblast growth factor (ODGF-1, -2, -3,-4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18,-19, -20, -21, -22, -23), colony stimulating factor, transforming growthfactor (e.g., TGF-β), vascular endothelial growth factors (VEGF),growth/differentiation factors (GDF-1, -3, -5, -6, -7, -8, -9, -9B, -10,-11, -15, -16), osteogenic proteins (OP-1=BMP-7, OP-2=BMP-8,OP-3=BMP-8b), bone growth hormone, parathyroid hormone (PTH), insulin,calcitonin, and the like. The proteins can also include proteinsassociated with cartilage, such as chondrocalcining protein; proteinsassociated with dentin, such as phosphosphoryn, glycoproteins and Glaproteins; or proteins associated with enamel, such as amelognin andenamelin. Structural proteins of interest for use in the presentinvention include, but are not limited to, fibrin, fibrinogen, keratin,tubulin, elastin, and the like. In one embodiment, blood proteins may beemployed, individually or together, in plasma or serum, e.g., serumalbumin.

In some embodiments, the therapeutic substance can further include anon-protein growth factor such as prostaglandins and statins (e.g.,Simvastatin, Lovastatin).

In one embodiment, the therapeutic substance is a growth factor such as,but not limited to, bone morphogenetic proteins, endothelial cell growthfactors, insulin-like growth factors, or the like, or a combinationthereof.

Any suitable amount of therapeutic substance may be used. For example,the amount of antimicrobial agent that is present in the flexible bonecomposite may be an amount sufficient to provide for a product that atleast reduces the growth rate of microbial organisms in the region ofthe product as compared to a control. In many embodiments, the amount ofantibiotic will be sufficient to provide for a zone of inhibition havinga diameter of at least about 10 mm, usually at least about 15 mm, asmeasured by the antibiotic activity assay as described U.S. Pat. No.5,968,253 to Poser et al., the entire content of which is expresslyincorporated herein by reference. The amount of therapeutic substanceused in the flexible bone composite can vary depending on factors suchas location of the repair, age and health of the patient, and the like,and can be determined by one skilled in the art.

Flexible bone composites including a therapeutic substance are alsouseful in the local delivery of such substance, e.g. to a physiologicalsite of interest. For example, flexible bone composites including anantimicrobial agent are useful for methods requiring release of anantimicrobial agent into a local environment over an extended period oftime, where the period of time is generally at least about 5, usually atleast about 10, and more usually at least about 20 days, where theflexible bone composites may release the antimicrobial agent into theirlocal environment for as long as 40 days or longer, depending on thespecific composition from which the product is prepared. Thus, theflexible bone composites including an antimicrobial agent find use asextended antimicrobial agent delivery vehicles, i.e. as antimicrobialagent depots, in which the local delivery of an antimicrobial agent foran extended period of time is desired. The subject compositions findparticular use as local antimicrobial agent delivery vehicles for bonetissue, particularly cancellous bone tissue.

In addition to, or instead of, therapeutic substances, flexible bonecomposites according to the invention can contain cells, particularlymononuclear cells, e.g., that are or can be differentiated (in vivo)into cells related to bone (i.e., osteogenic cells, precursors, orassociated materials such as osteoblasts, osteoblast precursors, bonemarrow cells, blood cells, connective tissue cells including smoothmuscle cells and the like, connective tissue progenitors, mesenchymalstem cells, collagen, fibrin, or the like, or a combination thereof).Flexible bone composites containing such cells, whether on thesurface(s) or in the interior, can advantageously be used as a matrixfor tissue engineering.

When utilized, the cells, whether allogenic, autogenic, or xenogenic,can be harvested and/or isolated by any known or conventional means,e.g., by centrifugation of bone marrow to isolate mononuclear cells,followed, for instance, by cell seeding and culturing in an osteogenicmedium.

The invention also includes methods for making a flexible bone compositeincluding a polymeric layer and a calcium-containing layer.

The flexible bone composite can be made by forming a polymeric layer asdescribed above, and depositing a first calcium compound on the firstside of the polymeric layer to form a first calcium-containing layer onthe polymeric layer. Any suitable method for affixing or physicallyand/or chemically attaching the calcium compound to the surface of thefirst side of the polymeric layer can be used. For example, in oneembodiment, the calcium compound can be affixed or physically and/orchemically attached to the first side of the polymeric layer by heatingthe polymeric layer for a time and a temperature sufficient to cause thecalcium compound disposed on the surface of the first polymeric layer tophysically and/or chemically attach to or adhere to the surface, e.g.,by heating the polymeric layer until it becomes tacky. In anothernon-limiting embodiment, the calcium compound is affixed or physicallyand/or chemically attached to the surface of a gel (which forms thefirst polymeric layer) to form a calcium-containing layer on the firstpolymeric layer. Optionally, the method of affixing or of physicallyand/or chemically attaching the calcium compound to the polymeric layercan include applying pressure.

In one embodiment, the flexible bone composite is made by forming apolymeric layer having a first side and a second side; contacting afirst calcium compound with the first side of the polymeric layer toform a first intermediate composite; and heating the first intermediatecomposite at a temperature sufficient to affix or to physically and/orchemically attach the first calcium compound to the first side of thepolymeric layer.

In one embodiment, the polymeric layers of the invention can beperforated prior to contact with the calcium compound.

In another embodiment, the invention includes a method for making aflexible bone composite including a perforated polymeric layer having afirst side and a second side, including: perforating a polymeric layerto form a perforated polymeric layer; heating the perforated polymericlayer; contacting a first calcium compound with the first side of theperforated polymeric layer to form a first intermediate composite; andallowing the first intermediate composite to cool to a temperaturesufficient to affix or to physically and/or chemically attach the firstcalcium compound to the first side of the perforated polymeric layer toprovide a first calcium-containing layer.

In one embodiment, the perforated polymeric layer is heated for a timeand a temperature sufficient to make the polymeric layer tacky.

Another method for making a flexible bone composite includes: casting asolution including a polymer and a solvent onto a release surface;allowing the solution to form a gel; contacting a calcium compound witha first side of the gel; and allowing the solvent to evaporate from thegel to form a flexible bone composite having a calcium-containing layeraffixed or physically and/or chemically attached to the first side ofthe polymeric layer.

Once prepared, the flexible bone composite may be dried under reducedpressure, packaged within an appropriate moisture and sterilized.

Another aspect of the present invention includes a kit or packagingsystem for storing, preparing, mixing, and/or administering compositesaccording to the invention.

The flexible bone composites according to the present invention can beused as or in implantable medical devices, and the like. Specifically,such applications or devices can include, but are not limited to, bonegraft containment (e.g., bone graft or bone graft substitutes) or bonevoid filler either alone or in combination with one or more otherconventional devices, which can include, but are not limited to, bonefixation plates (e.g., craniofacial, maxillofacial, orthopedic,skeletal, or the like); screws, tacks, clips, staples, nails, pins orrods, anchors (e.g., for suture, bone, or the like); scaffolds, scents,meshes (e.g., rigid, expandable, woven, knitted, weaved, etc.); sponges,implants for cell encapsulation or tissue engineering, drug delivery(e.g., carriers, bone ingrowth induction catalysts such as bonemorphogenetic proteins, growth factors, peptides, and the like,antivirals, antibiotics, etc.); monofilament or multifilamentstructures, sheets, coatings, membranes (e.g., porous, microporous,resorbable, etc.); foams (e.g., open cell or closed cell), screwaugmentation, cranial reconstruction; and/or combinations thereof. Whenused in or with implantable medical devices, the flexible bone compositeis preferably bioabsorbable and/or resorbable.

Any method for implanting the flexible bone composite can be used. Forexample, in one embodiment, the flexible bone composite can be laid intoa void, placed onto a bone or bones, rolled and packed into a void,folded and packed into a void, and the like.

In one embodiment, the invention includes a method for treating a hardtissue defect, e.g., bone or cartilage, in a patient in need thereof,including implanting a therapeutically effective amount of the flexiblebone composite of the invention into the defect. Such bone defectsinclude, but are not limited to, bone void, bone grafts, spine defects,an orthopedic defects, or maxillofacial defects. In one embodiment, thebone defect is a bone void.

In another embodiment, the invention includes a method for treating abone defect further including using a fixation device with the flexiblecomposite. Non-limiting examples of fixation devices include plates,screws, tacks, pins, rods, vertebral spacers, or any combinationthereof.

In another embodiment, the invention includes methods for aspiratingbone marrow in a patient in need thereof, including: implanting atherapeutically effective amount of the flexible bone composite into anarea proximal to the bone marrow. For example, in one embodiment, theflexible bone composite can be soaked in aspirated bone marrow andimplanted as described above.

EXAMPLES

Preferred embodiments of the present invention and comparativeembodiments will be illustrated by reference to the following examples,which are included to exemplify, but in no way limit, the scope of thepresent invention.

Example 1

About 2.94 g of 70:30 poly(L-lactide-co-ε-caprolactone) (PURASORB®, byPurac, Lincolnshire, Ill.) having an intrinsic viscosity of about 1.5dl/g was compression molded into a film using a Carver CompressionPress, Model No. 3895 (Carver, Inc., Wabash, Ind.) by placing thepolymer between stainless steel shims (about 0.12 mm) sprayed withPrice-Driscoll anti-stick mold release (Price-Driscoll Corp., Waterford,Conn.), and using about 0.11 mm brass shims to control the polymerthickness and using the following compression conditions: platen setpoint temperature, about 150° C.; load, about 10,000 kg; pump, about80%; dwell time, about 50 sec. After compression, the film was cooled ona cold plate to provide a polymeric layer having a thickness of about0.10 to about 0.12 mm.

Example 2

A polymeric layer was prepared from about 2.99 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 1, except thatKapton® polyimide release sheets (DuPont, Wilmington, Del.) (about 1 milthick) were placed between the polymer and the stainless steel shims.The resultant polymer film released easily from the sheets after coolingwith cold air to provide a polymeric layer having a thickness of about0.15 to about 0.18 mm and a diameter of 130 mm.

Example 3

A polymeric layer was prepared from about 2.96 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 2, except thatthe load was about 15,000 kg, and the dwell time was about 60 sec. Theresultant polymer film had a thickness of about 0.13 to about 0.15 mmand a diameter of about 143 mm.

Example 4

A polymeric layer was prepared from about 2.95 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 3, except thatthe load was about 20,000 kg. The resultant polymeric layer exhibitedbubbles, which was attributed to too thin a spread of polymer duringsetup. The polymeric layer had a thickness of about 0.13 to about 0.14mm and a diameter of about 146 mm.

Example 5

A polymeric layer was prepared from about 2.97 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 3, except thatthe platen set point was about 158° C. and the load was about 20,000 kg.The resultant polymer film had a thickness of about 0.11 to about 0.14mm and a diameter of about 149 mm.

Example 6

A polymeric layer was prepared from about 2.95 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 1, except thatthe platen set point was about 160° C., the load was about 24,000 kg,and the dwell time was about 70 sec. The resultant polymeric layer had athickness of about 0.11 to about 0.13 mm and a diameter of about 150 mm.

Example 7

A polymeric layer was prepared from about 3.40 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 6. Theresultant polymeric layer had a thickness of about 0.11 to about 0.13 mmand a diameter of about 160 mm.

Example 8

A polymeric layer was prepared from about 3.43 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 7 except thatthe dwell time was 75 sec. The resultant polymeric layer had a thicknessof about 0.11 to about 0.13 mm and a diameter of about 160 mm.

Example 9

A polymeric layer was prepared from about 3.40 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 8 to provide apolymeric layer having a thickness of about 0.11 to about 0.13 mm and adiameter of about 160 mm.

Example 10

A polymeric layer was prepared from about 3.51 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 7 to provide apolymeric layer having a thickness of about 0.11 to about 0.13 mm and adiameter of about 160 mm.

Example 11

A polymeric layer was prepared from about 3.49 g of 70:30poly(L-lactide-co-ε-caprolactone) as described in Example 7 to provide apolymeric layer having a thickness of about 0.11 to about 0.13 mm and adiameter of about 160 mm.

Example 12

Polymeric strips of 70:30 poly(L-lactide-co-ε-caprolactone) copolymer(thickness, about 0.1 mm; width, about 10 mm) were prepared according toExample 7 and placed in a Phosphate buffer solution (about pH 7.4)maintained at about 37° C. Strips were removed from the buffer and theirtensile strengths were determined. See the results in Table 1.

TABLE 1 Changes in tensile strength for a 70:30poly(L-lactide-co-ε-caprolactone) copolymer maintained in a phosphatebuffer solution (pH ~7.4). Tensile Strength Peak Yield Strength 0.2%Offset Modulus Weeks (MPa) (MPa) (MPa) 0 42.4 10.8 360.9 2 30.0 7.6141.0 4 27.8 7.1 133.9 8 15.7 6.5 147.9 12 5.2 3.8 117.9

Example 13

A polymeric layer of a 60:14:26poly(glycolide-co-dioxanone-co-trimethylene carbonate) was prepared asdescribed in Example 2, except the platen set point temperature wasabout 160° C., the load was about 24,000 kg, and the dwell time wasabout 70 sec.

Example 14

Polymeric strips of the 60:14:26poly(glycolide-co-dioxanone-co-trimethylene carbonate) copolymer ofExample 13 (diameter, about 0.1 mm; width, about 10 mm) were placed in aphosphate buffer solution (about pH 7.4) maintained at about 37° C.Strips were removed from the buffer and their tensile strengths weredetermined. The results are shown in Table 2.

TABLE 2 Changes in tensile strength for a 60:14:26poly(glycolide-co-dioxanone- co-trimethylene carbonate)copolymermaintained in a phosphate buffer solution (pH 7.4). Tensile StrengthPeak Yield Strength 0.2% Offset Modulus Weeks (MPa) (MPa) (MPa) 0 62.116.4 355.7 1 49.5 16.9 352.6 2 23.9 15.1 412.0

Example 15

The polymeric layer of Example 11 was perforated by placing thepolymeric layer over a soft substrate and punching about 1/16″ (1.5875mm) holes approximately 4-5 mm apart in the polymeric layer using a1/16″ punch and a mallet. The resultant perforated polymeric layer wasplaced between layers of a β-Ca₃(PO₄)₂ (available from Synthes, Paoli,Pa. under the tradename ChronOS™) and having a diameter of about 1.4 toabout 2.8 mm. The layered composition was placed in a stainless steelmold, and the mold was held together with medium paper binders. The moldwas placed in a convention oven at about 130° C. for about 15 minutes toprovide a flexible bone composite having a perforated resorbablepolymeric layer.

Example 16

A flexible bone composite was prepared as described in Example 15,except the polymeric layer was not perforated and the mold was heated ina convection oven at about 140° C.

Example 17

A flexible bone composite was prepared as described in Example 16,except the polymeric layer was slit (about 2 to about 3 mm in length)with a scalpel about 4-5 mm apart.

Example 18

A flexible bone composite was prepared as described in Example 15,except the ChronOS™ granules had a diameter of about 0.5 to about 0.7mm, and the mold was heated in a convection oven at about 145° C. forabout 20 minutes.

Examples 19-22 Effect of Surface Treatment on Composite Blood Uptake

Four types of flexible bone composites according to the invention werefabricated in the same general manner as in Example 18 (but with thediameter of polymeric layer from Example 11 being about 250 mm, thethickness of the polymeric layer varying from about 0.09 to about 0.17mm, and with the polymer weight exhibiting a change commensurate withthe increased diameter) and were annotated as Examples 19-22. Thecomposite of Example 19 contained a surface that was native, oruntreated, while the surfaces of composites of Examples 20-22 weretreated so as to make them more hydrophilic through exposure to oxygenplasma, to carbon dioxide plasma, and to a HYDROLAST™ treatment (whichis a plasma/grafting treatment process commercially available from ASTProducts, Inc., of Billerica, Mass., and which is described, inter alia,in U.S. Pat. Nos. 5,700,559, 5,807,636, and 5,837,377, the entiredisclosures of which are hereby incorporated by reference),respectively. The conditions for the oxygen and carbon dioxide plasmatreatments were similar to those used in the plasma portion of theHYDROLAST™ treatment process, which in these cases included RF plasma ata pressure of about 30 milliTorrs and at a power of about 250 Watts.

For each of the Examples 19-22, some flexible bone composites were usedas fabricated, while others were aged for about 21 days at about 45° C.The flexible bone composites of Examples 19-22, both as-fabricated andaged, were soaked in bovine blood under ambient conditions for about 30seconds to determine blood uptake levels. Table 3 below shows theresults. Mean uptake values represent the average of experiments onabout 15 separate samples.

TABLE 3 Bovine blood uptake for flexible bone composites according tothe invention - treated vs. untreated and aged vs. as-fabricated.Example Treatment Aged Mean Uptake 19 None Y 54% N 51% 20 O₂ plasma Y68% N 64% 21 CO₂ plasma Y 59% N 61% 22 HYDROLAST ™ Y 64% N 69%

Although the present invention is described with reference to certainpreferred embodiments, it is apparent that modification and variationsthereof can be made by those skilled in the art without departing fromthe scope or this invention, particularly as defined by the appendedclaims.

1.-29. (canceled)
 30. A method for making a flexible bone compositecomprising: forming a polymeric layer having a first side and a secondside; depositing a calcium compound on the first side of the polymericlayer to form a first calcium-containing layer on the polymeric layer;and affixing the calcium compound to the first side of the polymericlayer, wherein a majority of the external surface of the calciumcompound is not covered with polymer.
 31. The method of claim 30,wherein affixing the calcium compound to the first side of the polymericlayer comprises physically affixing the calcium compound to the firstside of the polymeric layer.
 32. The method of claim 30, whereinaffixing the calcium compound to the first side of the polymeric layercomprises chemically affixing the calcium compound to the first side ofthe polymeric layer.
 33. The method of claim 30, wherein affixing thecalcium compound to the first side of the polymeric layer comprisesheating the polymeric layer to a temperature sufficient to make thepolymeric layer tacky.
 34. The method of claim 30, further comprisingperforating the polymeric layer.
 35. The method of claim 34, wherein thepolymeric layer is perforated prior to depositing the calcium compoundon the first side of the polymeric layer.
 36. The method of claim 30,wherein forming the polymeric layer comprises casting a solutionincluding a polymer and solvent onto a release surface and allowing thesolution to form a gel, and wherein depositing the calcium compound onthe first side of the polymeric layer comprises contacting the calciumcompound with a first surface of the gel.
 37. The method of claim 36,wherein affixing the calcium compound to the first side of the polymericlayer comprises evaporating the solvent from the gel.
 38. The method ofclaim 30, wherein the first calcium-containing layer contains less thanabout 25% by weight of polymer.
 39. The method of claim 30, wherein thecalcium compound is in the form of granules.
 40. The method of claim 39,wherein the granules have a surface area of about 0.1 m²/g to about 100m²/g.
 41. The method of claim 39, wherein the granules have a meandiameter of about 0.05 mm to about 10 mm.
 42. The method of claim 30,wherein the calcium compound is porous.
 43. The method of claim 30,wherein the first calcium-containing layer is substantially free ofhydroxyapatite.
 44. The method of claim 30, wherein the calcium compoundcomprises a compound selected from the group consisting of CaHPO₄.nH₂O,α-Ca₃(PO₄)₂, α-bar-Ca₃(PO₄)₂, β-Ca₃(PO₄)₂, Ca₅(PO₄)₃OH, Ca₁₀(PO₄)₆(OH)₂,Ca₄O(PO₄)₂, CaP₄O₁₁, Ca₂P₂O₇, Ca(H₂PO₄)₂.nH₂O, Ca₈H₂(PO₄)₆.nH₂O, andcombinations thereof, where n is a number ranging from 0 to
 5. 45. Themethod of claim 30, wherein the polymeric layer comprises a syntheticresorbable polymer.
 46. The method of claim 45, wherein the syntheticresorbable polymer comprises repeat units selected from the groupconsisting of L-lactic acid, D-lactic acid, L-lactide, D-lactide,D,L-lactide, glycolide, a lactone, a lactam, ε-caprolactone,trimethylene carbonate, a cyclic carbonate, a cyclic ether,para-dioxanone, beta-hydroxybutyric acid, beta-hydroxypropionic acid,beta-hydroxyvaleric acid, and combinations thereof.
 47. The method ofclaim 30, further comprising depositing a calcium compound on the secondside of the polymeric layer to form a second calcium-containing layer.48. The method of claim 30, further comprising adding a therapeuticsubstance to the polymeric layer and/or the first calcium-containinglayer.
 49. A flexible bone composite made by the method of claim 30.